Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety

Abstract

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

Figure 1

Scanning electron microscope (SEM) images of (a) in-plane MNs (Daddona, 2002), (b) out-of-plane MNs (Donnelly et al., 2009b), and (c) combined in-plane and out-of-plane MNs (Jae-Ho et al., 2008).

Figure 2

SEM micrographs of variety of a hollow silicon MNs: (a) (i) PDMS microfluid chip integrated MN array with a (ii) microchannel entrance at the tip (Paik et al., 2004). (b) Cross- and circular-shaped HMNs with side-opening (Roxhed et al., 2008a). (c) Patch-like MN integrated dispensing unit (Roxhed et al., 2008b). (d) Array of MNs with 70 nm wall thickness and square arrangement (Rodriguez et al., 2005). (e) MN array integrated to a PZT pump (Bin et al., 2006). (f) Mosquito head and proboscis, the inset shows the magnified view of fascicle tip with labella retracted (Ramasubramanian et al., 2008).

Figure 3

Schematic representation of different methods of MN application across the skin. (a) Solid MNs applied and removed to create micropores followed by the application of a traditional transdermal patch. (b) Solid MNs coated with drug molecules applied for instant delivery. (c) Polymeric MNs which remain in skin and dissolve over time to deliver the drug within the MNs. (d) Hollow MNs for continuous drug delivery or body fluid sampling. Adapted from Arora et al. (2008).

Figure 4

Images of (a) MNs with ‘pockets’ of different shapes and sizes etched through the MN shaft (Gill & Prausnitz, 2007a). (b) Brightfield microscopy image of a single solid stainless-steel MN (Gill & Prausnitz, 2008).

Figure 5

SEM images of groove-embedded MNs (Han et al., 2009).

Figure 6

Dissolving MNs for transdermal drug delivery. (a) CMC pyramidal MNs encapsulating sulforhodamine B within the MN shafts, but not in the backing layer. (b) Skin surface showing MN delivered sulforhodamine B.

Figure 7

MN applicators from different companies. (a) MicroCor^™ applicator. Adapted from Gary (2009). (b) Zosano's Macroflux^® (i) applicator loaded with patch, (ii) applicator activated, (iii) patch delivered to the site. Adapted from Zosanopharma^® (2009). (c) AdminPatch^® MN array applicator. Adapted from Nanobiosciences^® (2009). (d) MicronJet^® MN device. Adapted from Nanopass^® (2009). (e) BD Soluvia^™ applicator. Adapted from BD (2009). (f) MTS-Rollers^™ applicator. Adapted from Microneedle^® (2009).